This proposal seeks 5 years of funding to continue the vitamin E (400 IU on alternate days), vitamin C (500 mg daily), and multivitamin (Centrum Silver daily) components of the Physicians' Health Study (PHS) II, extending average treatment and follow-up from 3.7 to 8.2 years. The PHS Ills an ongoing randomized, double-blind, placebo-controlled trial using a factorial design to evaluate the roles of Vitamin E, vitamin C, a multivitamin, and p-carotene in chronic disease prevention among 14,642 U.S. male physicians aged 50 years and older who have demonstrated excellent morbidity and mortality follow-up and high compliance. The PHS Ills uniquely positioned to clarify ambiguities regarding the roles of vitamin E in the primary prevention of prostate cancer and cardiovascular disease (CVD) among those at usual risk; the role of a multivitamin and vitamin C in the prevention of cancer and CVD; and all three agents in the prevention of eye disease and declines in cognitive function. After reviewing the progress of the trial and the unblinded data, the Data and Safety Monitoring Board unanimously recommended an extension beyond the trial's scheduled termination of funding in December 2002. The primary rationale for the Board's recommendation was the likelihood, at the end of current funding, of ambiguous results due to insufficient numbers of endpoints and an inadequate latent period, which they feared could result in considerable clinical confusion. Because recruitment and 3.7 years of treatment and follow-up have been supported by nearly $20,000,000 of industry funds, the proposal to extend PHS II represents an extremely cost-efficient way to provide either clear positive or definitive null results on which sound clinical and public health recommendations can be Dased for the use of these commonly consumed vitamin supplements. Given the gaps in knowledge this study is intended to address, we believe the proposed extension of this primary prevention trial in men at usual risk is timely, important, and will complement other ongoing clinical trials.